DESCRIPTION: (provided by the applicant): Malaria remains a major cause of death in humans worldwide. Despite the severity of this health problem, it is surprising that very little is known about the molecular mechanisms governing the invasion of Plasmodium into the liver at the subcellular level. Understanding sporozoite targeting to, entry into, and survival in the liver is of great importance to develop new approaches to fight the hepatic phase of malaria. Within minutes after transmission by an infected mosquito, malaria sporozoites are rapidly targeted to the liver and infect hepatocytes. To reach their initial site of multiplication in the mammalian host, the hepatocyte, sporozoites have to cross the continuous layer of sinusoidal cells. To accomplish this, sporozoites selectively recognize, invade, and pass through sinusoidal Kupffer cells, the stationary phagocytes of the liver. The broad long-term objective of this proposal is to understand the strategies mammalian Plasmodium species have developed to selectively recognize, actively invade, and safely passage through Kupffer cells, the professional stationary phagocytes of the liver, to reach their initial nurse cell in the host liver, the hepatocyte. We aim to characterize the molecular recognition mechanism between malaria sporozoites and Kupffer cells, to define the composition of the compartment that harbors the parasites, and to determine the effect of the parasites on macrophage activation in a rodent model. We will also examine the interaction between P. gallinaceum, whose exoerythrocytic forms can differentiate and multiply inside phagocytic cells, and avian Kupffer cells. Finally, we wish to compare the data obtained from these animal models with the interaction between human Kupffer cells and P. falciparum sporozoites.